5-142314456-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001127496.3(SPRY4):c.653C>A(p.Ser218Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00625 in 1,614,168 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0043 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 34 hom. )

Consequence

SPRY4
NM_001127496.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3O:1

Conservation

PhyloP100: 9.60

Variant links:

Genes affected

SPRY4 (HGNC:15533): (sprouty RTK signaling antagonist 4) This gene encodes a member of a family of cysteine- and proline-rich proteins. The encoded protein is an inhibitor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. Activity of this protein impairs the formation of active GTP-RAS. Nucleotide variation in this gene has been associated with hypogonadotropic hypogonadism 17 with or without anosmia. Alternative splicing results in a multiple transcript variants. [provided by RefSeq, Jun 2014]

SPRY4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013144106).

BP6

Variant 5-142314456-G-T is Benign according to our data. Variant chr5-142314456-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 50874.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS2

High AC in GnomAd at 653 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRY4	NM_001127496.3 linkuse as main transcript	c.653C>A	p.Ser218Tyr	missense_variant	2/2	ENST00000434127.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRY4	ENST00000434127.3 linkuse as main transcript	c.653C>A	p.Ser218Tyr	missense_variant	2/2	1	NM_001127496.3	P1	Q9C004-1
SPRY4	ENST00000344120.4 linkuse as main transcript	c.722C>A	p.Ser241Tyr	missense_variant	3/3	1
SPRY4	ENST00000643792.1 linkuse as main transcript	n.1335C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00429

AC:

653

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00641

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00683

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00446

AC:

1119

AN:

250986

Hom.:

AF XY:

0.00431

AC XY:

585

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00291

Gnomad FIN exome

AF:

0.00644

Gnomad NFE exome

AF:

0.00611

Gnomad OTH exome

AF:

0.00474

GnomAD4 exome

AF:

0.00645

AC:

9436

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00628

AC XY:

4568

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00405

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00298

Gnomad4 FIN exome

AF:

0.00644

Gnomad4 NFE exome

AF:

0.00753

Gnomad4 OTH exome

AF:

0.00394

GnomAD4 genome

AF:

0.00429

AC:

653

AN:

152306

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

300

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00359

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.00641

Gnomad4 NFE

AF:

0.00683

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00565

Hom.:

Bravo

AF:

0.00393

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00457

AC:

555

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00545

EpiControl

AF:

0.00640

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SPRY4: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31726455, 23643382) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in individuals with Kallman syndrome and controls was the same (Miraoui 2013). -

Amenorrhea

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Mar 08, 2021

- -

Hypogonadotropic hypogonadism 17 with or without anosmia

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 02, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.11

T;D

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

T;D

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

-0.26

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.5

D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

.;D

Vest4

0.36

MVP

0.92

MPC

1.3

ClinPred

0.023

GERP RS

5.5

Varity_R

0.81

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over